Regulation, biological effect, internal relationship, and control of steroid sex hormone synthesis and activity are complex and incompletely understood. However, the basics of this regulatory system are clear. It is known, for example, that the androgenic members of this class have nonaromatic "A" rings in the steroid nucleus, whereas the estrogens, as a group, contain aromatic "A" rings. It is also known that these hormones regulate cellular metabolism by binding to specific receptor sites in target cells. This observation has been of considerable importance in therapy for tumors related to sexually differentiated tissues. Depending on the presence or absence of the appropriate receptor, these tumors may or may not respond to therapy consisting in withdrawal of, or supply of, sex hormones. This treatment may be surgical, such as removal of the ovary to deplete the supply of estrogens, or medical such as by administration of the hormones or of their agonists or inhibitors.
Therapeutic surgery or administration of sex hormone medicaments is not limited to tumor treatment. Other metabolic processes are also related to these hormone levels. For example, it is now clear that the estrogen level influences considerably the mechanisms which regulate the formation or resorption of bone, and estrogen therapy has become conventional in the treatment of osteoporosis.
Thus, in a manner analogous to, for example, analgesia, compounds which influence the pathways regulating steroid sex hormone levels and activities have important therapeutic uses in a variety of contexts even though the mechanisms whereby they alter the hormone pattern are poorly defined. For example, 10.beta.-propynyl-substituted steroids, a class of inhibitors for aromatase ( an enzyme responsible for conversion of the nonaromatic androgens into the corresponding aromatized estrogens) has been found useful in treatment of hormone-dependent breast and endometrial cancers. These compounds have been shown to be suicide inhibitors of aromatase in vitro and have been shown to cause mammary tumor regression in vivo in rats. (See U.S. Pat. No. 4,322,416; Covey, D. F., et al, J Biol Chem (1981) 256:1076-1079 Johnston, J. O., et al, in Novel Approaches to Cancer Chemotherapy) Sunkara, P. S., ed (1984) Academic Press, pp. 307-358; Zimniski, S. J., et al. Eighth Annual San Antonio Breast Cancer Symposium (1985), Abstract No. 83: Brandt, M. E., et al, Endocrine Society Symposium (1985), Abstract No. 761. )
An additional enzyme significant in regulation of circulating and intracellular steroid hormone metabolism is the enzyme estradiol dehydrogenase (EC 1.1.1.62), otherwise called 17.beta.,20.alpha.-hydroxysteroid dehydrogenase (17.beta.-HSD). This enzyme in human placenta is a dimer of molecular weight 68 kd which catalyzes the interconversion of estrone and 17.beta.-estradiol using either NAD.sup.+ /NADH or NADP.sup.+ /NADPH as cofactors. It also catalyzes the conversion of 16.alpha.-hydroxyestrone to estriol. (Estriol production is considerably amplified during pregnancy, and since 17.beta.-HSD has been purified from the placenta, it is thought that formation of estroil may be its chief metabolic function.) Placental and other 17.beta.-HSD enzymes interconvert androstenedione and testosterone.
Diagram 1 summarizes the interrelationships of the steroid hormones whose levels are best known to be regulated by aromatase and 17.beta.-HSD. ##STR3##
Referring to Diagram 1, both estradiol and testosterone have more potent activities with respect to estrogenicity and androgenicity, respectively, than their corresponding oxidized forms estrone and androstenedione. Therefore regulation of 17.beta.-HSD results in regulation of the effective level of steroid sex hormones. In premenopausal women, aromatase is effective in the ovary in converting both androstenedione and testosterone to their respective aromatized forms and estradiol production from testosterone is, therefore, independent of the activity of 17.beta.-HSD (for a given level of testosterone). On the other hand, in postmenopausal women, most estrogen synthesis is extraglandular and is by conversion of androstenedione to estrone. This form of estrogen biosynthesis has been shown in a wide variety of tissues, and effective estrogen levels depend on the ability of 17.beta.-HSD to convert the estrone to estradiol.
The conventional steroid numbering system is used in the following discussion and hereinbelow, unless otherwise specified. This system is shown under the Definitions section below.
Because the aromatization of the "A" ring utilizes a mechanism which involves oxidation at C-19 of the steroid system, compounds containing modifications proximal to this carbon have been studied with respect to impacting aromatase activity. On the other hand, the oxidation catalyzed by 17.beta.-HSD is at C-17, which carbon is a member of the "D" ring. In analogy to the approach taken with respect to aromatase, potential suicide inhibitors of 17.beta.-HSD have been suggested which contain modifications proximal to C-17, including modification at C-16 by substitution with a methylene group (Thomas, J. L., et al, J Biol Chem (1983) 258:11500-11504) and by utilizing a 20.alpha.-acetylene substitution (Tobias, B., et al, J Biol Chem (1982) 257:2783-2786). These inhibitors have been characterized in terms of their binding affinity (Km) their turnover number (Vmax) and by their partition ratio (R.sub.p). Each compound has a particular pattern of these variables; no single pattern is necessarily ideal for every metabolic condition.
It has now been found that an additional class of compounds capable of influencing steroid sex hormone metabolism is characterized by an open "D" ring to provide a hydroxymethyl or .alpha.-oxo substituent to the steriod "C" ring, which substituent can be further substituted either to provide suicide inhibition capacity, or to serve as a direct inhibitor of the enzyme or as an inhibitor to binding of the normally produced sex hormones to the appropriate receptor. Both male and female hormone analogs are useful in this way; the oxidation state of the "A" ring may or may not be significant with respect to the capacity of these compounds to perform a regulatory function according to a particular mechanisms. Accordingly, the compounds of the invention add to the repertoire of available therapeutic tools in treatment of conditions requiring regulation of hormone metabolism.